Arch Dis Child: first published as 10.1136/adc.48.3.169 on 1 March 1973. Downloaded from

Review article

Archives of Disease in Childhood, 1973, 48, 169.

Some physiological and clinical aspects of * H. K. A. VISSER From the Department of Paediatrics, Medical Faculty and Academic Hospital, Sophia Children's Hospital and Neonatal Unit, Rotterdam, The Netherlands Puberty is usually taken to be the process of embryonic life. Cytogenetics, experimental embry- maturation of the sexually immature child into the ology and endocrinology, steroid biochemistry, sexually mature adolescent, while the term adoles- and clinical medicine have contributed to the rapid cence has been used to describe that period of increase in our knowledge during the past decades. human development when secondary sex charac- Much of our information has been derived from teristics have appeared completely but full maturity animal experiments and the results of these experi- has not been reached. Recently psychologists and ments very often, but not always, can be applied child psychiatrists have been using the term adoles- to the human. cence particularly to refer to the emotional and

behavioural development and the changes in social Early differentiation of and genital copyright. interaction during this period of life. In this organs. The structure of the undifferentiated review we shall use, as Tanner (1962), the words is identical in male (XY) and female (XX) puberty and adolescence without distinction. embryos until the 7th week. In the 7th week in This review will emphasize physiological rather the XY-embryo the medullary tissue of the un- than clinical aspects of puberty. Several excellent differentiated gonad begins to develop in a fetal books and review papers on the subject are available testis. About two weeks later in the XX-embryo (Tanner, 1962, 1969, 1970; Falkner, 1966; Marshall the cellular cortex starts to differentiate in a fetal and Tanner, 1968; Donovan and van der Werff . Interstitial cells of Leydig are visible at http://adc.bmj.com/ ten Bosch, 1965; van der Werff ten Bosch, 1965; about 8 weeks and it is generally accepted that their Hubble, 1969; Prader, 1971; Gold and Douvan, secretions are responsible for further male differen- 1969), but adolescent medicine has been a long tiation of genital ducts and external genital organs. neglected field ofmedicine on the borderline between The fetal testis acts in three ways: it induces paediatrics and internal medicine. It should not development of the external genital organs, it be regarded as a new specialty, but be integrated stimulates differentiation of the Wolffian duct, into paediatrics. Studying the anatomy and physio- and it inhibits differentiation of the Miullerian duct. on September 26, 2021 by guest. Protected logy of adolescence, the paediatrician will gain more Our knowledge in this field is mainly based on the insight into the pathology of this period of life, and brilliant animal experiments of Jost (1958). Induc- he will understand better the problems of boys and tion of the development of the external genital girls in the period between childhood and adult organs is an androgenic hormonal effect that can life. be reproduced by administering . Physiologically the substance most probably respon- Sexual maturation and differentiation during sible is testosterone, secreted by the Leydig cells adolescence of the fetal testis. Jost's experiments have shown Maturation of gonadal secretory function and the that male duct differentiation is promoted by a development of secondary sex characteristics during factor which is secreted by the fetal testis and acts adolescence are the final phase of a continuous unilaterally. The effect cannot be reproduced by process of that starts in early systemic injections of testosterone. For this reason one may argue that the 'duct male organizing *The Windermere Lecture given at the joint meeting of the substance' is not a common androgenic steroid. British Paediatric Association and Scottish Paediatric Society, Aviemore, 1972. However, testosterone secreted by the Leydig cells 169 Arch Dis Child: first published as 10.1136/adc.48.3.169 on 1 March 1973. Downloaded from

170 H. K. A. Visser

ANDROGENIC EXT. GENJITALIA

DIFFERENTIATION 1,7OLFFIAN DUCTS (INT. GENITALIA) SUPPRESSION MtILLERIAN DUCTS

IMPRINTING BRAIN

EXT. GED;ITALIA

NO DIFFERENTIATION WOLPFIAN DUCTS DIFFERENTIATION MULLERIAN DUCTS (INT. GENITALIA) T IMPRINTING BRAIN

FIG. 1.-Schematic presentation ofprenatal sexual differentiation (adaptedfrom Prader, 1971; for explanation see text). copyright. of the fetal testis probably will be present locally 1970), oestradiol (Knorr, Kirschner, and Taylor, (around the testis) in high concentrations which 1970), and gonadotropins have been estimated in cannot be achieved by systemic injections of testo- plasma and urine of prepubertal children. Several sterone. authors have reported that prepubertal boys Inhibition of the development of the Fallopian respond to administration of human chorionic tubes and uterus from the Miillerian ducts cannot gonadotropin (HCG) for 4 to 15 days with an http://adc.bmj.com/ be accomplished by testosterone. The factor increased excretion of urinary testosterone (Loras, involved is still unknown; it certainly is not an Ollagnon, and Bertrand, 1966), or with an increase . Fig. 1 summarizes these events. Only in plasma testosterone levels (Saez and Bertrand, the presence of will induce the develop- 1968; Rivarola, Bergada, and Cullen, 1970). ment of male external genitalia. In the presence of Zachmann and co-workers (1971) have shown functioning fetal testes the Mullerian ducts involute, recently that even after a single dose of HCG while the Wolffian ducts develop (ductus deferens, prepubertal boys respond with an increased excre- epididymis, seminal vesicles). In the absence of tion of urinary testosterone. This procedure can on September 26, 2021 by guest. Protected testes the Wolffian ducts disappear, the Miillerian be used to study the function of the testis before structures develop (Fallopian tubes, uterus, upper puberty. Apparently, mature Leydig cells are not part of vagina). Female development of the genital required to produce testosterone in response to ducts occurs not only in the presence of an ovary, HCG. but also when no gonad is present. During recent years several studies have reported values for plasma and urinary gonadotropin con- Maturation of gonadal secretory function. centrations during childhood and pubertal develop- In the male, Leydig cells become inactive a few ment (Johanson et al., 1969; Raiti et al., 1969; weeks after birth and change into mesenchymal Rifkind et al., 1970; Lee, Midgley, and Jaffe, 1970; cells. During childhood the ovary and testis Penny et al., 1970), but until very recently little histologically show no signs of activity. However, or no information was available on plasma concen- using sensitive techniques, small amounts of testo- trations of gonadotropins and gonadal sterone (Frasier and Horton, 1966; Forest and during the stages of puberty. Grumbach and co- Migeon, 1970; Degenhart, Visser, and Wilmink, workers (Burr et al., 1970; August, Grumbach, Arch Dis Child: first published as 10.1136/adc.48.3.169 on 1 March 1973. Downloaded from

Some physiological and cilinicalV. . aspects of1- puberty 171 PLASMA and Kaplan, 1972; Sizonenko et al., 1970; Jenner LH FSH ng/ml et al., 1972) have now published data on 30- 6- plasma 25- 5- concentrations of gonadotropins (FSH, follicle- LH stimulating hormone, and LH, luteinizing hormone) 2-0- 4- and gonadal hormones (testosterone, 17,-oestradiol) 15- 3- FSH in relation to pubertal development in the male and 10- 2- female. These results are schematically shown in 0.51 1 - Fig. 2 and 3. Though such cross-sectional studies I I I I 1 2 3 4 5 ADULT PLASMA LH FSH ng/ml PLASMA TESTOSTER(ONE 2-5-5- LH 20- 4 600 - ng/nni 500- 1 5- 3- FS 400 - 1-0- 2- _ 300- 0-5- 1- 200 - 1001 1 2 3 4 5 I.I 5I I I I I 1713 1 2 3 4 5 ADULT OESTRADIOL pg/ml STAGE OF PUBERTY 60- 8--12-13-14- 15 ADULT 50- BONE AGE (YEARS) 40- (a) 30- 20- copyright. PLASMA 10 LH FSH ng/mI 5- 25- 1 2 3 4 5 2O- 4- LH STAGE OF PUBERTY 16- 3- FSH X UNDETECTABLE < 10-] 2- 7 pg/mi 0.5- 1- FIG. 3.-Schematic presentation of changes in plasma LH, FSH, and 17fl-oestradiol during puberty in the female. http://adc.bmj.com/ 5 7 9 11 13 15 17 ADULT Vertical bars indicate periods of greatest changes. Based on data from the cross-sectional study of Jenner et al. PLASMA (1972). The curves represent our own interpretation of TESTOSTERONE the data. 600 ng/mi

500- TESTICULAR 400- VLUME /-/ have their well-known limitations and do not necessarily show the sequence of events in indivi- 300- dual boys and girls, these data are the best available on September 26, 2021 by guest. Protected 200- at this moment and certainly describe the general 100- trend in hormonal events during puberty. 5 7 9 11 13 In boys pubertal development apparently starts 15 17 ADULT with an increase in the plasma concentration of BONE AGE (YEARS) luteinizing hormone (LH). There is an increase (b) of testicular volume and an initial rise of plasma testosterone (2nd stage of puberty). Subsequently FIG. 2.-Schematic presentation of changes in plasma there is an increase in the plasma concentration of LH (luteinizing hormone), FSH (follicle-stimulating follicle-stimulating hormone (FSH). During the hormone), and testosterone during puberty in the male, 3rd to 5th stage ofpuberty there is a gradual increase related to (a) stage of puberty, (b) bone age. Vertical both and bars indicate periods of greatest changes. Based on data of LH FSH, while a sharp rise in plasma from cross-sectional studies of Burr et al. (1970) and testosterone, associated with further testicular August et al. (1972). The curves represent our own inter- enlargement, takes place during the 3rd to 4th pretation of the data. stage of puberty. Arch Dis Child: first published as 10.1136/adc.48.3.169 on 1 March 1973. Downloaded from

172 H. K. A. Visser Wieland, Yen, and Pohlman (1970) estimating Both values subsequently decrease to low levels. serum LH and testosterone in pooled sera of boys in Note the typical increase of plasma oestradiol different age groups also found that an increase of during the , with a peak just before circulating LH precedes an increase in serum , and the increase of both oestradiol and testosterone. Animal studies (Woods and Simpson, progesterone during the . Both steroids 1961) and studies on patients with hypogonadotropic are secreted by the corpus luteum. Crooke et al. hypogonadism (Martin, 1967; Lytton and Kase, (1967) and Crooke, Morell, and Butt (1968) have 1966) support the concept that the early pubertal tried to reproduce this sequence of events in the enlargement of the testes is due to the effect of LH. treatment of infertile patients. They gave a single In the female the first hormonal event of puberty injection of FSH on day 1, and 9 or 10 days later is an increased secretion of FSH, though there is an injection of chorionic gonadotropin (HCG; this also a slight early increase in plasma LH. In their is an LH-like hormone); subsequently ovulation studies on serum gonadotropins in prepubertal followed. girls, Penny et al. (1970) found that FSH levels It has to be emphasized that most adolescent girls increased at an earlier age (5 to 8 years) than LH after go through a period with irregular, levels (9 to 10 years). Fig. 3 shows a continuous anovulatory cycles. This period of adolescent increase of both gonadotropins and 17,B-oestradiol sterility in the female was noticed long ago, and has in relation to stage of puberty. Jenner et al. been found in many species. (1972) report good correlation with bone age. Animal experiments have shown that the control Note the remarkably good correlation between hor- of cyclic release of gonadotropins by the pituitary monal changes and bone age in boys (Fig. 2). Iso- gland is situated in the hypothalamus. The lated premature development of the (prema- pituitary gland itself is bipotential: the pituitary of ture ) is usually found in young girls. a male adult rat when grafted under the hypothala- There are no other signs of sexual maturation; mus of an adult female rat will be able to release except in some patients minimal oestrinization of the gonadotropins cyclically. In the rat there is a

vaginal smear. Growth and bone maturation are critical period (a few days before birth until 10 copyright. normal for age. Jenner et al. (1972) reported slightly C raised concentrations of plasma oestrogens in some - BASAL BODY TEMPERATURE...... patients. Plasma concentrations of LH and FSH 3&7 have been found normal (Penny et al., 1970) or 3 _5 somewhat increased (Kenny et al., 1969; Jenner et al., 1972). These findings indicate increased PLASMA OESTRADIOL 400- oestrogen production by the rather than OESTRADIOL pg/ml 300- PLASMA http://adc.bmj.com/ increased end organ sensitivity as the cause of this PROGESTERONE condition. Usually the enlargement is 200 20 ng/mj 100 - transient, but it may persist until the onset of ...... I puberty at a normal age. It is tempting to specu- late that there is early (transient) activation of the PLASMA 70- hypothalamopituitary-gonadal axis, but if so, the 0 FSH, LH 60 MENSES system must be operating at a very low level. nIU/mI 60

50- on September 26, 2021 by guest. Protected Sexual differentiation of hypothalamus and 40- pituitary. As just discussed, the maturation of 30- gonadal secretory function requires the activity of 20- LH both gonadotropins, LH and FSH, in both sexes. 10- ...FSH However, there is a great difference in the secretory I pattern of the gonadotropins in the mature adult -16-12-8-4 0 4 8 12 16 male and female. In the male plasma concentra- t DAYS OF tions of FSH and LH are relatively constant. In OVULATION the normal adult female there is a typical cyclic FIG. 4.-Schematic presentation of changes in plasma pattern, which is illustrated in Fig. 4. During the gonadotropins (LH, FSH) and plasma oestradiol and first part of the follicular phase (around the 12th progesterone during a normal menstrual cycle. Based on day before ovulation) there is a rise in FSH, data from Ross et al., 1970 and Van de Wiele et al., followed by a decline, and then a rise again, together 1970. The curves represent our own interpretation of the with a sharp increase of LH at the time of ovulation. data. Arch Dis Child: first published as 10.1136/adc.48.3.169 on 1 March 1973. Downloaded from

Some physiological and clinical aspects ofpuberty 173 INHIBITORY EFFECT CNS is of a noncycic type. One single injection of (LIMBIC SYSTEM); DRUGS etc 1 ,ug testosterone given to the newborn female rat 'CYCLIC 'TONIC causes sterility at adult age. This effect has been RELEASE RELEASE AREA' AREA' called 'early androgen syndrome'. In experiments using electrical stimulation Barraclough and Gorski (1961) localized the androgen-sensitive region in the preoptic area of the hypothalamus. Electrical stimulation of this area causes ovulation in normal female adult rats but not in 'androgen-sterilized' rats. Barraclough and Gorski suggest that this area controls cyclical discharge of gonadotropins to cause ovulation. In androgen-treated female animals LH secretion could be induced by electrical stimulation of the median eminence, the ventro- medial area of the hypothalamus. According to Barraclough and Gorski, this area is responsible for OVUIARY tonic discharge of small amounts of gonadotropin (LH), which maintain oestrogen secretion but can- not independently initiate ovulation. In the male this area is involved in the feedback control of LH- release by circulating androgens. Fig. 5 and 6 (TESTOSTERONE)OESTRESGENEN schematically represent the interrelations between UTERUS hypothalamus-pituitary gland and gonads. Though in the human such control areas have not been SEC. SEX CHARACTERISTICS anatomically localized, the same system of dual

hypothalamic control of secretion of gonadotropins copyright. FIG. 5.-Cyclic release of gonadotropins in the female. Schematic presentation of the interrelations between is probably operating in the female. There is no hypothalamus (CNS), pituitary gland, and ovary in the female. There is cyclical release of gonadotropins LH NO FUNCTIONAL 'TONIC REGULATiNG 'CYCLIC RELEASE RELEASE CNS and FSH (see Fig. 4). In the rat the 'cyclical release AREA' AREA' INFLUENCE (?) area' is located in the preoptic area of the hypothalamus; this area is 'androgen-sensitive'. The 'tonic release area' is located in the median eminence of the hypothalamus http://adc.bmj.com/ (Barraclough and Gorski, 1961). Such areas have not been located in the human. There is feedback regulation between gonad and hypothalamus-pituitary (long-loop system). In the rat, feedback regulation between pituitary and hypothalamus has been proposed (short-loop system); it is not known if this can be applied to the human. FSH- AH and LH-RH: gonadotropin-releasing hormone(s), a decapeptide, whose isolation, structural determination, and

synthesis recently has been completed (Schally et al., 1971). on September 26, 2021 by guest. Protected Note inhibitory effect on ovulation by some drugs, and regudatory effects of CNS on hypothalamic areas. For further explanation see text.

CHARAT days after birth) during which the central nervous system becomes sexually differentiated (Pfeiffer, 1936; Barraclough and Gorski, 1961; Swanson and van der Werff ten Bosch, 1963, 1964; Harris, 1964; FIG. 6.-Noncyclical release of gonadotropins in the male. Barraclough, 1966). Administration of testosterone Schematic presentation of the interrelations between and testis in the to the female rat during this period leads to a 'male hypothalamus (CNS), pituitary gland, male. See also Fig. 5. In the human the 'tonic release central nervous system. At adult age type' area'3 probably is located in the median eminence of the ovaries in such animals do not show cyclic variations hypothalamus. There is feedback-regulation between in activity, but usually develop follicular cysts. gonad and hypothalamus-pituitary. For further explana- Gonadotropin secretion in these animals apparently tion see text. Arch Dis Child: first published as 10.1136/adc.48.3.169 on 1 March 1973. Downloaded from

174 H. K. A. Visser evidence that in the human excess of androgens at CNS an early age causes sterility. Female patients STRESS etc treated for congenital adrenal hyperplasia usually have normal ovarian function at adolescence. In some of these patients cystic ovaries have been reported. It is possible that the critical period for 'androgen-sterilization' in the human is at a much earlier period in embryonic life and androgen concentrations required may be higher. Role of adrenal glands in puberty. During puberty there is increased urinary excretion of 17- ketosteroids in both sexes. Until the age of about 16 years there is no sex difference, afterwards excretion in the male becomes higher than in the female (Knorr, 1965; for a review see Tanner, 1969). This increase in urinary 17-KS excretion in both sexes is mainly due to increased production of adrenal androgens (Visser, 1966; Visser and Degenhart, 1966). A rise in plasma concentrations of (DHA) and andro- sterone in both sexes during puberty has been reported (Migeon et al., 1957; Rosenfield and Eberlein, 1969). The adrenal component of adolescence is under the control of the pituitary gland, since it is absent in the patient with hypo- pituitarism. It has been postulated that the copyright. increased production of adrenal androgens as puberty approaches might be the result of stimula- SEC. SEX CHARACTERISTICS tion by a specific pituitary hormone ('androgen- (MAINLY IN FEMALE) stimulating hormone') which is synergistic with FIG. 7.-Schematic presentation of the interrelations ACTH, but so far this substance has not been between hypothalamus (CNS), pituitary gland, and isolated. There is no adolescent spurt in the adrenal cortex. ACTH-RH -- ACTH-releasing hor- production of cortisol and aldosterone (calculated mone. ACTHstimulates production ofcortisol, androgens, http://adc.bmj.com/ per m2 body surface), and this argues against an and, to some extent, aldosterone. There is feedback action increased ACTH stimulation as the primary cause of of cortisol. For further explanation see text. the adolescent spurt in adrenal androgen production. One might speculate that some factor, possibly a (mainly dehydroepiandrosterone (DHA); Visser hormone, modifies the response of the adrenal and Degenhart, 1966). Plasma concentrations of glands to ACTH when puberty starts. However, DHA and androsterone are increased in some

the fact that in some patients with precocious patients (Conly, Sandberg, and Cleveland, 1967). on September 26, 2021 by guest. Protected sexual hair (premature ), central disorders Plasma gonadotropins are normal (Penny et al., are found as in patients with true sexual precocity, 1970) or low (Kenny et al., 1969). The syndrome is in favour of the existence of a specific pituitary must be caused by premature activation of the 'adrenal androgen stimulating hormone'. Fig. 7 adrenal cortex, which normally takes place in illustrates the interrelations between hypothalamus, adolescence; there is increased production of pituitary gland, and adrenal cortex. adrenal androgens before the hypothalamo- In children, pubic and axillary hair may develop pituitary-gonadal axis is activated. at an early age without the appearance of the other Hormonal changes during puberty not only symptoms of sexual maturation. Bone maturation reflect quantitative changes in production of and height are slightly advanced in most patients. gonadal and adrenal steroids, but also changes in The syndrome is called 'premature adrenarche' or biosynthesis and metabolism of steroids, which are 'pubarche'. It is usually seen in girls. Urinary due to maturation and/or activation of enzyme excretion of 17-ketosteroids is moderately raised systems. In the bull the ratio of androstenedione due to increased excretion of adrenal androgens and testosterone in spermatic vein blood decreases Arch Dis Child: first published as 10.1136/adc.48.3.169 on 1 March 1973. Downloaded from

Some physiological and clinical aspects ofpuberty 175 during puberty, indicating an increase in 17oc- infantile rats, removal of the ovaries is followed by dehydrogenase activity in the testis (Lindner, an increase in plasma gonadotropins (Donovan and 1961). Available data do not indicate if such a van der Werfften Bosch, 1965). These and other data change occurs in men (Frasier and Horton, 1966; suggest that a feedback mechanism between hypo- Forest and Migeon, 1970). It is very difficult thalamus, pituitary, and gonads is operating before to differentiate the amounts of steroids produced puberty (Donovan and van der Werff ten Bosch, by gonads and adrenals and, moreover, there is 1959, 1965). At the onset of puberty the sensitivity peripheral conversion of androstenedione to testo- of the hypothalamic feedback-receptor cells is sterone and vice versa (Degenhart et al., 1970). changing; these cells, until that time very sensitive Teller (1967) reported evidence of changes in the to minute amounts of circulating gonadal hormones, metabolism of androgens during puberty. become less sensitive and subsequently greater amounts of gonadotropins are released by the Timing of puberty. The mechanism of the pituitary gland via the increased release of FSH- initiation of puberty is an intriguing problem. and LH-releasing hormone by the hypothalamus. The rate of growth and development and the onset This stimulates the maturation of gonadal secretory of puberty are genetically determined, as is illus- functions, and plasma concentrations of oestradiol trated in the similarity of the growth curves and the and testosterone increase. Ultimately a feedback- small difference in time of puberty between identical system is re-established, but at another (higher) twins (Tanner, 1962). There is a good correlation 'gonadostat' level. This concept is illustrated by between onset of puberty and menarche of mothers and daughters. |CNS| L I The syndrome of true in /-Z young children shows that maturation of gonads and secondary sex characteristics can start at a much earlier age than the usual time of onset of puberty.

Experiments with rats have shown that pituitary copyright. glands of prepubertal animals when grafted under the hypothalamus of hypophysectomized adults start very soon to function in a normal adult fashion. Testes or ovaries of prepubertal animals when transplanted to castrated adults almost immediately function normally in an adult way (Harris and

Jacobsohn, 1952; Harris, 1964; Donovan and van der http://adc.bmj.com/ Werff ten Bosch, 1965). Therefore, the control of puberty must be situated in the hypothalamus or other areas ofthe central nervous system. Donovan and van der Werfften Bosch (1956, 1965) and other OESTROGENSJ 1F experimental endocrinologists have shown that PROGESTOGENS J in the rat destructive lesions in the anterior and PRE-PUBERTY ONSET OF PUBERTY ADULT posterior part of the hypothalamus cause precocious FIG. 8.-Schematic presentation of the change infeedback- puberty. The animal experiments by Barraclough sensitivity of the hypothalamus at the onset of puberty. on September 26, 2021 by guest. Protected (1966) and others, as discussed in the previous Thickness of arrows denotes amount of hormones or section on sexual differentiation of the hypothala- strength of signalfrom CNS. Note that after completion mus, also provide strong evidence for the location of puberty, the adult's feedback system is re-established of hypothalamic centres controlling the release of at a higher 'gonadostat' level-see text. gonadotropins before and after puberty. In the human, precocious puberty often is caused by Fig. 8. There is evidence for feedback-regulation of lesions in the posterior part of the hypothalamus. FSH and LH release by oestrogens and progesterone As mentioned before, in prepubertal children in the adult female. Feedback-regulation of LH small amounts of gonadotropins and gonadal release by androgens and of FSH and LH release by hormones can be estimated in plasma and urine. oestrogens has been reported in the adult male. See In children with gonadal dysgenesis plasma Fig. 4, 5, and 6 (for a review see Odell and Moyer, gonadotropin levels are raised compared with 1971). normal prepubertal children of the same age Recently Grumbach and co-workers have pro- (Penny et al., 1970; Jenner et al., 1972). In vided strong evidence for such a change in feedback- Arch Dis Child: first published as 10.1136/adc.48.3.169 on 1 March 1973. Downloaded from

176 H. K. A. Visser sensitivity at the onset of puberty in the human is a good correlation between the degree of ossifica- (Kuhn, Grumbach, and Kaplan, 1969, 1972; Kelch, tion of the skeleton (skeletal maturation) and the Kaplan, and Grumbach, 1972). Clomiphene-citrate, onset of puberty. Bone age is one of the criteria an anti-oestrogen with weak oestrogen activity, for estimating developmental age as opposed to stimulates gonadotropin release in the adult. The chronological age. Androgens and oestrogens precise mechanism of action is not known, but accelerate growth and skeletal maturation. Excess clomiphene probably acts by competing with of endogenous and exogenous sex hormones, as in steroids (oestrogens ?) at hypothalamic receptor sites precocious puberty and in the treatment of tall (Bardin, Ross, and Lipsett, 1967). Kulin et al. girls and boys, advances growth and skeletal administered clomiphene-citrate in a dosage of 100 maturation. Pubertal development usually does mg/M2 per day during 7 days to adult males: urinary not start until there is a certain degree of skeletal excretion of FSH and plasma testosterone concen- maturation. Many environmental factors affect trations increased. The same dosage given to body growth, skeletal maturation, and the onset of prepubertal children (boys and girls) apparently puberty. Apparently there is a correlation of brain suppressed FSH excretion and (in boys) plasma maturation and maturation of the body as a whole. testosterone. Clomiphene suppressed FSH and LH At a certain critical point pubertal development excretion in prepubertal children when given in starts. Recently Frisch and Revelle (1969, 1970) very small amounts of 0 1-1 0 mg/m2 per day. have suggested that there is a relation between 3 girls in the early stages of sexual maturation were the onset of puberty and a critical body weight. given 100 mg/m2 per day for 1 week. In one girl Early and late maturing girls have menarche at the FSH excretion increased, in another FSH excretion same weight (about 48 kg), but height is different. decreased, in the third no change was observed. Frisch and Revelle propose that at a critical body These results can be explained by different sensitivity weight metabolic rate is changing, which alters the of the hypothalamic feedback-receptor cells to feedback sensitivity at the hypothalamic level. steroids. Clomiphene has weak oestrogenic activity; Some relation between body weight and onset of apparently in prepubertal children the hypothalamic puberty has been found in the rat (Kennedy and cells are very sensitive to minute amounts of Mitra, 1963). copyright. oestrogens. Failure of clomiphene to raise plasma During the past century in the industrial coun- testosterone levels in prepubertal boys has also been tries a constant trend toward earlier maturation reported by Cathro, Saez, and Bertrand (1969). and earlier onset of puberty in children has been In another study (Kelch et al., 1972) the Cali- observed (secular trend; for a review see Tanner, fornian workers have shown that very small 1962, 1969). Children of all ages have been grow- amounts of oestrogens (ethinyl oestradiol 2-3 ,ug/ ing taller and heavier; this process starts in infancy m2 per day for 4-7 days) in prepubertal children (Thomson, 1954), and probably already before http://adc.bmj.com/ significantly suppress urinary FSH excretion. birth. The onset of puberty has become earlier During puberty a higher dosage of ethinyl oestra- at a rate of about 1 year per 25 calendar years. diol was required to lower FSH excretion. These Many factors such as socioeconomic class, illness, studies provide the first direct data in the human and nutrition affect the rate of growth and the onset to support the concept that decreased sensitivity of puberty. In poor social classes the onset of of the 'gonadostat' is the initiating factor for the puberty is later. Children with many sibs may

onset of puberty in man. grow less fast than children in small families. on September 26, 2021 by guest. Protected The factors that cause the change in hypothalamic Animal experiments support these findings in steroid sensitivity are unknown, but it is very likely the human. Rats nursed in small litters grow that there is a release of inhibition by central faster and reach sexual maturity earlier than rats nervous system 'input'. For many years the nursed in large litters (Kennedy and Mitra, 1963). pineal gland was thought to regulate the onset of There is evidence that acceleration of growth is puberty. Pineal tumours have been found in child- connected with earlier maturation of the brain ren with precocious puberty. In animals a pineal (Lat, Widdowson, and McCance, 1960). During gland hormone, melatonin, has been found to inhibit recent years many investigations have shown the gonadal maturation (Cohen et al., 1964; for a lasting effect of undernutrition at early age on recent review see Axelrod, 1970). The physio- body growth and brain development (see for logical significance for the human is unknown. instance Winick, 1968, 1969; Barnes et al., 1968; The central nervous system 'input' that controls Stoch and Smythe, 1968; Smart and Dobbing, the onset of puberty is in some way related to 1971; Dobbing, 1972). The causes of the trend the maturation of the organism as a whole. There toward earlier maturity are not clear, but it is well Arch Dis Child: first published as 10.1136/adc.48.3.169 on 1 March 1973. Downloaded from

Some physiological and clinical aspects ofpuberty 177 accepted that better nutrition is one of the most puberty and their families usually need careful important factors. The effect of better nutrition attention ofthe child psychologist, child psychiatrist, starts in early life, during the intrauterine period and social worker. For an extensive review of and infancy. It is tempting to speculate that in the precocious puberty the reader is referred to van der human, as in animals, there is a critical period Werff ten Bosch (1969) and Prader (1971). during which environmental factors affect brain development, body growth, and timing of puberty. In the human this period probably occupies the Somatic and psychic maturation during last part of prenatal life and some period (1 to 2 adolescence years) after birth. In summary, the rate of growth and development Adolescent growth spurt and secondary sex and the time of onset of puberty are determined by characteristics. There are many somatic changes genetic and environmental factors. Normally during puberty and most of these are different in puberty starts at a critical stage of general develop- both sexes. Boys and girls are different before ment and brain maturation. The 'trigger' might puberty, but during puberty the differences become be the attainment of a critical body size. The much greater. There is growth of the gonads and continuous trend toward earlier maturation and genitalia; appearance of secondary sex characteris- onset of puberty in the industrialized countries can tics; a remarkable increase in body growth-body be explained by the constant improvement of size and body shape (the adolescent growth spurt)- environmental conditions at an early age. and there are great changes in body composition. From the foregoing discussion it will be evident These somatic changes during adolescence have that it is difficult to define the term 'early' or 'pre- been reviewed in great detail by Tanner (1962, cocious' puberty. One has to consider the great 1969). The Table summarizes mean ages for individual variation in the age at which puberty girls and boys when different stages of pubertal begins and the phenomenon of continuous earlier development are reached, as reported by several maturation during childhood. In the industrialized authors (Reynolds and Wines, 1948, 1951; Nicolson copyright. countries the onset of puberty in girls earlier than and Hanley, 1953; Van Wieringen et al., 1968; 8 years of age and in boys earlier than 10 years of Marshall and Tanner, 1969, 1970). The peak of age could be defined as precocious puberty. the adolescent growth spurt in height is reached Signs of puberty in such children require extensive in the average girl at stage B3 and PH3, and in the investigations and a careful long-term follow-up. average boy at stage G4 and PH4. In more than 90% in girls and about 50% in boys, The relation between the growth spurt and precocious puberty is caused by idiopathic early hormonal changes during puberty is still not clear. http://adc.bmj.com/ activation of the hypothalamo pituitary-gonadal Testosterone in boys and oestrogens in girls axis. No direct causal factor can be found. stimulate growth. The difference in growth Radioimmunoassay methods for the estimation of spurt between boys and girls is probably due to plasma gonadotropins are now available and this is testosterone. Adrenal androgens probably do not most important for the differentiation between play an important role; in patients with premature 'true' and 'pseudo' precocious puberty. Medical adrenarche there is usually only a small increase treatment, with the intention of interfering with the in height and skeletal maturation. The role of abnormal secretion of gonadotropins and/or gonadal growth hormone may be important. Androgens on September 26, 2021 by guest. Protected hormones and of stopping the most undesirable and oestrogens enhance the release of growth effects on growth and bone maturation, has been un- hormone in response to insulin-induced hypogly- successful. Medroxyprogesterone acetate (Depo- caemia. In male patients with delayed puberty Provera) probably suppresses the pituitary release of and anorchia, treatment with androgens led to gonadotropins. Menstrual bleeding usually stops. higher plasma growth hormone concentrations There is certainly some effect on several male and (Deller, Plunket, and Forsham, 1966; Martin, female secondary sex characteristics. It is very Clark, and Connor, 1968; Illig and Prader, 1970). difficult to evaluate the effect on bone maturation Kaplan, Frasier, and Costin (1969) reported a high and ultimate height, but results so far have been plasma growth hormone response to hypoglycaemia disappointing. Unfortunately the drug has some in children with precocious puberty. inhibitory effect on the pituitary-adrenal axis Epiphysial closure at the end of the growth (Mathews, Abrams, and Morishima, 1970; Sadeghi- spurt is probably caused by testosterone and Nejad, Kaplan, and Grumbach, 1971). Apart oestrogens. Treatment of tall boys with testo- from medical treatment, children with precocious sterone and tall girls with oestrogens is followed by Arch Dis Child: first published as 10.1136/adc.48.3.169 on 1 March 1973. Downloaded from

178 H. K. A. Visser TABLE Mean ages (yr) for girls and boys at which different stages of pubertal development are reached. Stages of development of genitalia (G2-G5), breasts (B2-B5), and (PH12-PH5) as described by Tanner (1962, 1969)

B2 B3 B4 B5 PH2 PH3 PH4 PH5 Menarche Country Girls Reynolds and Wines (1948) 10-8 11-4 12-2 13-7 11 0 11.9 12 5 13-9 12-9 U.S.A. Nicolson and Hanley (1953) 10-6 11-2 - 13-9 11-6 12-5 13-2 - 12-8 U.S.A. Van Wieringen et al. (1968) 11 0 12-1 13-4 15-2 11-3 12-2 13-3 14-9 13-4 TheNetherlands Marshall and Tanner (1969) 11-2 12-2 13-1 15-3 11-7 12-4 13-0 14-4 13-5 England

G2 G3 G4 G5 PH2 PH3 PH4 PH5, Country Boys Reynolds and Wines (1951) 11-5 12-7 13-4 17-3 12-2 13-3 13-9 16-1 U.S.A. Nicolson and Hanley (1953) 11-8 13-1 13-8 15-2 U.S.A. Van Wieringen et al. (1968) 11 0 13-2 14-2 15-9 11-8 13-5 14-4 16-0 The Netherlands Marshall and Tanner (1970) 11 6 12 9 13 8 14 9 13 4 13-9 14-4 15 1 England closure of the epiphyses. It is possible that other during adolescence, particularly of the limbs hormones, such as growth hormone, are involved. (Tanner, 1965). This is usually accompanied by Ossification of the skeleton, as measured by fat loss in boys, but not in girls. Total body fat skeletal maturity, is advanced in girls over boys. and lean body mass have been estimated in adoles- At birth girls are already some weeks ahead of boys cents using K40 measurements in a 'whole body in bone age, and there is a gradual increase until the counter'. Fig. 9 schematically presents the results copyright. onset of puberty when the difference has increased of Forbes (1963, 1964, 1965), Forbes and Hursh to about 2 years. In general, girls enter puberty (1963), and Allen, Anderson, and Langham (1960). about 2 years earlier than boys, and as a consequence a boys grow for longer time than girls. This is WEIGHT (kg) partly responsible for some somatic differences 70-i between the sexes, such as greater adult height and longer limbs in the male. Tanner et al. (1959) http://adc.bmj.com/ found that bone age in XO-karyotype children 60- before puberty was not different from normal XX- females; XXY-boys had the same bone age as 50- XY-boys. Thus, the relative retardation of matura- tion in boys is apparently connected with the 40- presence ofthe Y-chromosome. Precocious puberty is more often seen in girls than in boys, while 20- delayed puberty is usually seen in boys. In these on September 26, 2021 by guest. Protected boys with constitutional delay of growth and 20- puberty, bone age usually is-retarded compared / FAT with chronological age; there is no evidence for 10 - hormonal disorders. The explanation of the advanced skeletal maturation and earlier onset of puberty in girls remains obscure. 10 20 30 40 50 AGE YEARS Changes in body composition during adoles- curves the in cence. Changes in body composition during FIG. 9.-Schematic illustrating changes body composition (total body fat and total lean body mass) adolescence are most impressive (for a review see during adolescence. Based on data from Forbes, 1963, Owen and Brozek, 1966). Using radiographic 1964, 1965; Allen et al., 1960; Anderson, 1963. Curves and anthropometric methods, changes in bone, represent our own interpretation of the data and illustrate muscle, and fat diameters can be measured. the general trend in changes. There is great individual There is a spurt in muscle and bone diameters variation. Arch Dis Child: first published as 10.1136/adc.48.3.169 on 1 March 1973. Downloaded from

Some physiological and clinical aspects ofpuberty 179 During puberty there is a sharp increase in lean environmental factors may play a more important body mass in both sexes. In the female this role than biological factors. The social-cultural increase in lean body mass starts about 2 years climate of the young age group in our modem earlier than in boys and is accompanied by a western society, with its emphasis on sex and gradual increase in total body fat. In the male competition, can be a great strain for children with there is an initial decrease in body fat, followed by the syndrome of short stature and delayed puberty. a gradual increase. These findings confirm the Psychotherapy and (in boys) carefully controlled clinical impression of the relatively fat prepubertal intermittent treatment with anabolic steroids may boy who changes during puberty to a slender be helpful. adolescent. Maximal values for lean body mass are It is not my intention to discuss the aspects of reached earlier in the female. At age 18 the male: psychic maturation during adolescence in detail. female ratio for lean body mass is greater than that The interested reader is referred to Tanner (1962) for weight or height (Forbes, 1965). This explains and Gold and Douvan (1969). The paediatrician differences in performance in athletics and other should be aware of the psychological aspects of sports between both sexes. adolescent development. His understanding can As Forbes (1964, 1965) clearly points out, these be of immense help to parents, teachers, and changes in body composition during adolescence adolescents themselves. It is my impression, and have important nutritional implications. Nutri- I am supported by child psychologists and child tional daily requirements for growth purposes alone psychiatrists, that the dramatic present-day presen- are considerable and different for both sexes. tation of adolescent problems, as expressed by such phrases as 'rebellious youth' and 'generation-conflict' Psychic maturation during adolescence. is largely exaggerated. Mass media over-emphasize Adolescence is not only characterized by great and the admittedly important problem of minority rapid somatic changes connected with the process groups of adolescents. Most adolescents, I believe, of sexual maturation, but adolescent development are willing to respect their parents' standards and also comprises a most important process of psychic to rely on their judgement and guidance. While copyright. maturation. There are qualitative and quantita- slowly finding their way to autonomy, the adoles- tive changes in the sexual drive, which affect the cents' ties to parents and family are more intense behaviour of the adolescent. The adolescent is than we usually think. Adults have to learn and to slowly changing his role of dependent child to that understand the physiology of adolescence and have of the independent, autonomous adult. There is a to provide optimal conditions for the growth and shift in personal relationships and a search for development of their children during this period of identity, while social interactions are changing. life. It is certain that the 'facts of nature' present http://adc.bmj.com/ There is a continuous increase of intellectual per- some specific problems: great individual variation formance, which probably reaches its maximum in in chronological age when puberty starts, advanced the early 20's, after the adolescent years. Abstract maturation in girls as compared with boys, and the thinking develops, which explains the interest of trend toward accelerated growth and maturation the adolescent in philosophical, ethical, and reli- and earlier onset of puberty but at the same time gious issues. extension of the period of learning and dependency.

There is no good evidence for an adolescent on September 26, 2021 by guest. Protected growth spurt in intellectual functions. A slight It was with a deep sense of appreciation that I difference in results of intellectual performance accepted the honour of addressing the British Paediatric Association and the Scottish Paediatric Society by giving tests has been found in relation to physical matura- the Windermere Lecture. Most of the work which I tion. Children who are physically advanced for have reviewed here has been carried out by my fellow their age score better results than children who are human biologists and only a fraction by myself and my less mature. At a later age such differences prob- co-workers. I am particularly grateful to Professor Van der Werfften Bosch (Department ofEndocrinology, ably disappear. Remarkably few data are avail- Growth and Reproduction, Medical Faculty, Rotterdam) able. In children with precocious puberty psycho- for help, and Professor Grumbach (Department of logical and behavioural maturation usually is not Pediatrics, University of California, San Francisco) clearly advanced and is related to chronological for sending me unpublished work of his group and age. giving permission to discuss it here. Some behavioural tests, for instance on interests and social attitudes, also show differences between RaRaNCES Allen, T. H., Anderson, E. C., and Langham, W. H. (1960). Total early and late maturers, and between girls and boys. body potassium and gross body composition in relation to age. It should be emphasized that cultural and other Yournal of Gerontology, 15, 348. Arch Dis Child: first published as 10.1136/adc.48.3.169 on 1 March 1973. Downloaded from

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